Preparation containing a combination of 5-methylisoxazole-4-carboxylic acid-(4-trifluoromethyl)-anilide and N-(4-trifluoromethylphenyl)2-cyano-3-hydroxycrotonic acid amide

ABSTRACT

A solid composition comprising 5-methyl-4′-trifluoromethyl-4-isoxazole carboxanilide and N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonic acid amide, suitable for treatment of immunological and cancerous diseases.

DESCRIPTION

Combination preparation, comprising5-methyl-4′-trifluoromethyl-4-isoxazolecarboxanilide andN-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide

The European Patent Application with the publication number 0 013 376disclosed that 5-methyl-4′-trifluoromethyl-4-isoxazolecarboxanilide(compound 1) has antirheumatic, antiinflammatory, antipyretic andanalgesic activity and can be employed against multiple sclerosis.Pharmaceuticals which comprise the active compound5-methyl-4′-trifluoromethyl-4-isoxazolecarboxanilide are administeredorally in doses of from 25 mg to 150 mg.

The European Patent Application with the publication number 0 217 206reports that N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide(compound 2) has immunomodulating properties and is suitable fortreating chronic graft-versus-host disease and autoimmune diseases, inparticular systemic lupus erythematosus. Pharmaceutical preparationswhich comprise a compound 1 or compound 2 can be administered in a doseof from 10 to 200 mg, preferably, however, of from 50 to 100 mg, in thecase of an injection solution in ampoule form (intravenous), inparticular based on compound 2 or a salt thereof, of from 1 to 30 mg,preferably of from 5 to 10 mg, and, in the case of rectaladministration, of from 50 to 300 mg, preferably of from 100 to 200 mg.However, the oral administration of 5 mg or 10 mg of compound 1 orcompound 2, in each case on its own, per kg does not have anysignificant effect.

It has been found that a combination preparation, which comprisescompounds 1 and 2, exhibits surprisingly advantageous immunosuppressiveeffects. The addition of small quantities of compound 2 to the mainactive component compound 1 results in a marked increase in the activityof the combination preparation. Due to the magnitude of this effect, theuse of this combination can be extended to areas which hitherto remainedclosed to an immunosuppressive therapy using the individual components.Furthermore, the reduction in the dose, without any decreased activity,leads to greater safety in use. At the same time, it can be assumed thata reduction in the dose in association with unchanged activity willenable the therapy costs to be lowered substantially.

The invention relates, therefore, to a solid preparation which comprisescomponent 1) 5-methyl-4′-trifluoromethyl-4-isoxazolecarboxanilide,component 2) N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamideand/or a physiologically tolerated salt ofN-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide and/or astereoisomeric form ofN-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide and 3) apharmaceutical excipient,

wherein the content of component 1 is from 2 to 20 mg and the content ofcomponent 2) is from 0.3% to 50% of that of component 1).

The compounds 5-methyl-4′-trifluoromethyl-4-isoxazolecarboxanilide andN-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide can be producedusing known methods (EP 0 529 500).N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide having thefollowing structural formula

is employed as such and/or a physiologically tolerated salt ofN-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide and/or astereoisomeric form ofN-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide in thepreparation according to the present invention.

Examples of suitable physiologically tolerated salts ofN-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide are alkalimetal, alkaline earth metal or ammonium salts, including those ofphysiologically tolerated organic ammonium bases.

The novel solid preparation is suitable, for example, for treating

-   -   acute immunological events, such as sepsis, allergy and        graft-versus-host reactions and host-versus-graft reactions    -   autoimmune diseases, in particular rheumatoid arthritis,        systemic lupus erythrematosus and multiple sclerosis    -   psoriasis, atopic dermatitis, asthma, urticaria, rhinitis and        uveitis    -   type II diabetes    -   hepatic fibrosis, cystic fibrosis and colitis    -   cancerous diseases, such as lung cancer, leukemia, ovarian        cancer, sarcoma, Kaposi's sarcoma, meningioma, intestinal        cancer, lymph node cancer, brain tumours, breast cancer,        pancreatic cancer, prostate cancer or skin cancer.

The novel solid preparation can also comprise combination packs orcompositions, in which the components are juxtaposed and can thereforebe administered simultaneously, separately or at graded time intervalsto one and the same human or animal body. According to the invention,components 1 and 2 can also be present in juxtaposed, separate medicinalforms, in particular when the spatial dimensions of the medicinal formsmake administration more difficult. This applies, in particular, to theoral forms, since elderly patients often have an aversion to largetablets or capsules. It is imperative that the separate, juxtaposedmedicinal forms are arranged so that they can be taken at the same time.In this context, different forms, for example a tablet and a capsule,can also be present alongside each other.

The invention furthermore relates to the use of a combination ofcompounds 1 and 2 for preparing a pharmaceutical which exhibits ahyperadditive increase in the immunosuppressive effect.

The invention furthermore relates to a process for producing the novelpreparation, wherein compounds 1 and 2 and a pharmaceutical excipientare processed into a pharmaceutical administration form.

The novel solid preparation can be present as a dosage unit in the formof medicinal forms such as capsules (including microcapsules), tablets(including coated tablets and pills) or suppositories, with it beingpossible, when capsules are used, for the capsule material to exercisethe function of the excipient and the content to be present, forexample, as a powder, gel, emulsion, dispersion or solution. However, itis particularly advantageous and simple to prepare oral (peroral)formulations with the two compounds 1 and 2, which formulations comprisethe calculated quantities of the active compounds together with eachdesired pharmaceutical excipient. A corresponding formulation(suppository) for rectal therapy can also be used. Transdermaladministration in the form of ointments, creams or oral administrationof solutions which comprise the novel preparation, is likewise possible.

In addition to the active compounds, ointments, pastes, creams andpowders can also comprise the customary excipients, for example animaland vegetable fats, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, talc, zincoxide, lactose, silicic acid, aluminum hydroxide, calcium silicate andpolyamide powders, or mixtures of these compounds.

The tablets, pills or granulate bodies can be prepared by customaryprocesses, such as compressing, dipping or fluidized bed processes orboiler coating, and comprise excipients and other customary auxiliarysubstances such as gelatin, agarose, starch (e.g. potato, corn or wheatstarch), cellulose, such as ethyl cellulose, silicon dioxide, varioussugars, such as lactose, magnesium carbonate and/or calcium phosphates.The coating solution is normally composed of sugar and/or corn syrup andusually also contains gelatin, gum arabic, polyvinylpyrrolidone,synthetic cellulose esters, surface-active substances, plasticizers,pigments and similar additives corresponding to the state of the art.Any customary flowance agent, lubricating agent or glidant, such asmagnesium stearate and mold lubricant can be used for producing thepreparations.

Preferably, the preparations are in the form of casing/core tablets ormultilayer tablets, with compound 2 being located in the casing or inthe core or in a layer, while compound 1 is located in the core or inthe casing or in another layer. Compounds 1 and 2 can also be present indelayed-release form, or be adsorbed to release-delaying material or beenclosed in the release-delaying material (for example material of thiskind based on cellulose or polystyrene resin, for example hydroxyethylcellulose). Delayed release of the active compounds can also be achievedby providing the layer in question, or the compartment, with customarycoatings which are insoluble in gastric juice.

The dose to be used naturally depends on different factors, such as theliving subject (i.e. human or animal) to be treated, age, weight,general state of health, the severity of the symptoms, the disease to betreated, any accompanying diseases, (if present) the nature of theaccompanying treatment with other pharmaceuticals, or the frequency ofthe treatment. In general, the doses are administered several timesdaily and preferably from once to three times daily. In this context,the quantities of individual active compound which are used are based onthe recommended daily dose of the particular individual active compoundand should, in the combination preparation, generally be from 10% to100% of the recommended daily dose, preferably from 20% to 80%, inparticular 50%. The appropriate therapy with the novel combinationsconsequently comprises, for example, the administration of one, two or 3individual doses of the preparation composed of

-   1) 5-methyl-4′-trifluoromethyl-4-isoxazolecarboxanilide in a    quantity of from 2 to 20 mg, 2 to 19.9 mg, 4.5 to 19.5 mg, 4.85 to    19 mg, 5 to 18 mg, 5 to 15 mg, 5 to 10 mg, 5 to 9.9 mg, 5 to 9.7 or    5 to 9.0 mg and-   2) N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide in a    quantity of from 0.3% to 50%, preferably of from 0.5% to 20%, in    particular of from 0.8% to 15%, particularly preferably of from 1%    to 10%, very particularly preferably of from 1% to 5%; in each case    based on the content of    5-methyl-4′-trifluoromethyl-4-isoxazolecarboxanilide, and-   3) a pharmaceutically tolerated excipient.

The percentage values (%) of compounds 1 and 2 refer in each case topercent by weight.

The quantities of the active components naturally depend on the numberof individual doses and also on the disease to be treated. Theindividual dose can also be composed of several dosage units which areadministered simultaneously.

EXAMPLE 1

Pharmacological Tests

Adjuvant-induced arthritis, modification in accordance with Perper(Proc. Soc. exp. Biol. Med. 137, 506 (1971))

Male rats of a Lewis strain (Moellegard, Denmark) having a body weightof from 160 to 210 g are used as the experimental animals. On the 1stday, the animals are injected subcutaneously, into the tail root, withcomplete Freund's adjuvant containing a suspension of Mycobacteriumbutyricum in heavy paraffin oil (Difco; 6 mg/kg in paraffin oil; Merck).Compounds 1 and 2 are suspended in carboxymethyl cellulose (1% in water)and this suspension is administered orally. The compounds areadministered once daily from the 1st to the 12th day of the experiment.The paw volume and the arthritis index are determined on the 18th day.

The severity of the disorder is determined by measuring the volumes ofboth hind paws. The measurement is carried out by the water displacementmethod, using a 2060 plethysmometer (Rhema-Labortechnik, Hofheim,Germany). In addition, the arthritis index is determined on the 18th dayafter injection.

Determination of the arthritis index: 1. Ears 0.5 point for each ear onwhich redness appears and nodules are formed 2. Nose   1 point forconnective tissue swelling 3. Tail   1 point for the emergence ofnodules 4. Front paws 0.5 point for each paw in which at least oneinflammation appears on a joint 5. Hind paws   1 point for slightinflammation (swelling)   2 points for a medium-strength inflammation  3 points for a massive inflammatory reaction

Animals forming a control group are only given the solvent (1%carboxymethyl cellulose in water). 6 animals are used for each dose andin the control group. A reduction in the increase in paw volume and adecrease in the arthritis index, as compared with the untreated controlgroup, are used as the criteria for an effect having been achieved.

Table 1 shows the results. The total quantity of compounds 1 and 2 isconstant in each of the different experiments.

TABLE 1 Decrease in Decrease in Compound 1 Compound 2 paw volumearthritis index (mg/kg of rat) (mg/kg of rat) (%) (%) 10 0 74 58 9.9 0.193 66 9.7 0.3 94 71 9.0 1.0 95 66 5 0 10% increase 12% increase 4.850.15 10  5 4.5 0.5 46 35

Both at 5 mg/kg and at 10 mg/kg of rat live weight, the effect of thenovel preparation is markedly intensified by increasing quantities ofcompound 2. Therefore, small additional quantities of compound 2 lead toa marked intensification of the effect of the novel preparation.

1. A solid composition comprising: a first component comprising5-methyl-4′-trifluoromethyl-4-isoxazolecarboxanilide; a second componentcomprising a compound of formula I

or a stereoisomeric form of the compound of formula I, or aphysiologically tolerated salt of the compound of formula I; and a thirdcomponent comprising a pharmaceutically tolerated excipient; wherein thefirst component has a concentration from about 2 to about 20 mg and thesecond component has a concentration from about 0.3% to about 15% of thefirst component.
 2. The composition as claimed in claim 1, wherein theconcentration of the second component is from about 1% to about 10% ofthe first component.
 3. The composition as claimed in claim 1, whereinthe concentration of the second component is from about 1% to about 5%of the first component.
 4. The composition as claimed in claim 1, whichcomprises a first component and a second component in a form for rectalor oral administration.
 5. The composition as claimed in claim 1,wherein the concentration of the second component is from about 0.5 % toabout 15 % of the first component.
 6. The composition as claimed inclaim 1, wherein the concentration of the second component is from about0.8 % to about 15 % of the first component.
 7. A process for thepreparation of a pharmaceutical composition of claim 1, which comprisesprocessing components 1, 2, and 3 into a pharmaceutically acceptableform for administration.
 8. A method of treating an immunologicaldisease comprising administering to a patient in need of such treatment,a therapeutically effective amount of a solid composition comprising afirst component comprising5-methyl-4′-trifluoromethyl-4-isoxazolecarboxanilide; a second componentcomprising a compound of formula I

or a sterioisomeric form of the compound of formula I, or aphysiologically tolerated salt of the compound of formula I; and a thirdcomponent comprising a pharmaceutically tolerated excipient; wherein thefirst component has a concentration from about 2 to about 20 mg and thesecond component has a concentration from about 0.3% to about 15% of thefirst component.
 9. The method of claim 6, wherein the compositionproduces a hyperadditive increase in the immunosuppressive effect.
 10. Amethod according to claim 6, wherein the immunological disease is anacute immunological disease.
 11. A method according to claim 8, whereinthe acute immunological disease is sepsis, allergy, graft-versus-hostreaction, or host-versus-graft reactions.
 12. A method according toclaim 6, wherein the immunological disease is an autoimmune disease. 13.A method according to claim 10, wherein the autoimmune disease isrheumatoid arthritis, systemic lupus erythrematosus, multiple sclerosis,psoriasis.
 14. A method of treating a disease comprising administeringto a patient in need of such treatment, a therapeutically effectiveamount of a solid composition comprising a first component comprising5-methyl-4′-trifluoromethyl-4-isoxazolecarboxanilide; a second componentcomprising a compound of formula I

or a stereoisomeric form of the compound of formula I, or aphysiologically tolerated salt of the compound of formula I; and a thirdcomponent comprising a pharmaceutically tolerated excipient; wherein thefirst component has a concentration from about 2 to about 20 mg and thesecond component has a concentration from about 0.3% to about 15% of thefirst component, and wherein the disease is atopic dermatitis, asthma,urticaria, rhinitis, uveitis, type II diabetes, cystic fibrosis,colitis, or hepatic fibrosis.